The overall goal of this project is to construct a detailed, quantitative model of neocortical cells, by integrating our knowledge of their dendritic geometry with data concerning the distribution of voltage- and calcium- dependent conductances as well as the dynamics and distribution of intracellular calcium throughout the cell and the effect of fast excitatory NMDA and non-NMDA synapses and slower GABAergic synapses on the patterning of action potentials. Our principal tools are numerical computer simulations. We plan to address a number of issues. (1) The standard 1-D cable model assumes that the electrotonic structure of cells does not change in response to input. However, in vivo neurons are immersed into a network of spontaneously active cells. Preliminary simulations show that this synaptic bombardment can change somatic input resistance and time-constant by more than one order of magnitude. Massive synaptic input, such as during sensory stimulation, can similarly affect the spatio-temporal behavior. How will neuromodulators, such as noradrenaline and ACh, targeting potassium and calcium currents, affect spatio-temporal integration? (2) We will design realistic models of NMDA and non-NMDA input, including their voltage-dependencies, different sensitivities to glutamate and different time courses of the synaptic currents. How can the multiplicative effect on visually-driven responses observed in the visual cortex and the fact that NMDA input is preferentially activated by high-frequency input be derived from these properties? (3) Cortical cells are classified as either regular spiking (pyramidal cells), fast spiking (smooth stellate cells) and intrinsically bursting cells (layer V pyramidal cells). We will model these differences, with emphasis on trying to understand the observed structure-function relationship. (4) Electrophysical evidence suggests the existence of active sodium and calcium conductances in at least part of the ascending portion of the apical dendritic tree. What is their function? Modeling this requires us to understand the effect of calcium buffering, diffusion and pumping on the electrical activity of cells with extended dendritic trees and spines.